DESCRIPTION (Applicant's Description): Candidate: The proposed research plan will explore the function of HER4 as a potential differentiation factor in human breast cancer. The training that Dr. Sartor will receive under the direct supervision of Dr. H. Shelton Earp during the award period will significantly enhance her development in basic science methodology critical to the success of an independent investigator. Dr. Sartor's long-term career goals are to become an academic radiation oncologist who can combine multidisciplinary breast cancer patient care with a study of the biology of human breast cancer. Her ultimate goal is to determine the significance of the epidermal growth factor receptor family of receptors in human breast cancer with regard to prognosis, treatment response, recurrence, and to develop new therapeutic strategies that target EGFR family members. Funding of the requested award would ensure the protected time away from clinical responsibilities necessary to ensure further lab training in molecular oncogenesis research. Environment: Support from this proposal comes from the UNC Lineberger Comprehensive Cancer Center and the Departrnent of Radiation Oncology. Dr. Sartor is provided space in Dr. Earp's laboratory as well as use of the core facilities of the Cancer Center and the UNC Breast Cancer SPORE. Support will include equipment, reagents, and consumables for the project. Funding of this proposal will ensure that 75 percent of the candidate's time will be devoted to the proposed research. Research: Our preliminary studies, as well as those of others, demonstrate that ligands that activate HER4 can cause differentiation and decrease proliferation of human breast cancer cells. However, HER4 has not been proven to have a direct and causal role in differentiation. Therefore, we propose a series of experiments using stably expressed HER4, EGFR:HER4 chimera and dominant negative HER4 mutants to determine whether activation of HER4 causes differentiation. We will define the contest in which HER4 is involved in a differentiation signal, paying particular attention to partnership with other EGFR family members, studied under the influence of EFG family member ligands which activate HER4. We will then explore the downstream signal transduction pathways of HER4 involved in differentiation. These avenues of investigation of HER4 will help us to understand more about the complex and critically important EGFR family members in breast cancer, and may lead to the discovery of HER4 as an important prognostic factor and potential target for novel therapeutics.